title: Pharmacokinetics of bosentan in routinely treated Japanese pediatric patients with pulmonary arterial hypertension.
abstract: We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.
authors.affiliation: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Taguchi
authors.forename: Fukiko
authors.initials: F
authors.lastname: Ichida
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hirono
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyawaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Chisato
authors.initials: C
authors.lastname: Akita
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Nakayama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Saji
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kato
authors.forename: Isao
authors.initials: I
authors.lastname: Horiuchi
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D001499:Bayes Theorem; D001835:Body Weight; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004347:Drug Interactions; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000097:blood / Q000150:complications; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy*; D007223:Infant; D007231:Infant, Newborn; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010879:Piperazines; D011687:Purines; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D000077300:Bosentan